Gastrin is a peptide hormone that signals through the G-protein coupled receptor (GPCR) CCK2R, and has a variety of effects including stimulation of gastric epithelial cell proliferation and acid secretion by parietal cells (Yassin R R, Peptides 20:885-98, 1999). It has also been characterized as a factor in the progression of gastric cancers and presents a potential target for therapies that neutralize its function (Smith et al. Gut 47:820-24, 2000).
Gastrin is a hormone produced in the digestive tract of many species, including humans. Normal adults produce gastrin in only one cell type—the G cells which line the gastric mucosa in the antral portion of the stomach (Ganong, Review of medical physiology. Norwalk, Conn., Appleton & Lange, 1995). Food intake stimulates the G cells to produce gastrin. Specifically, distension of the lumen of the stomach or the presence of peptides and amino acids in the stomach stimulate gastrin secretion. There is also a neural pathway for gastrin release as the sight or smell of food may stimulate (through the Vagus nerve) release of gastrin.
Once secreted, gastrin has a range of activities on the digestive tract. The primary roles of gastrin in a normal adult are to stimulate acid production by the parietal cells of the stomach and to act as a trophic factor for cells lining the gastrointestinal tract. Gastrin also serves other secondary roles in the digestive tract such as stimulating pepsin and pancreatic enzyme release, and gall bladder contraction and small intestine motility. Gastrin is produced in a precursor form of 101 amino acids called pre-pro-gastrin. This protein goes through a series of cleavage steps to generate several different proteins of varying length (Mulholland et al., Surgery 103:135-47, 1988). Additional post-translational steps include glycine addition and amidation. Gastrin may be expressed as pre-pro-gastrin, pregastrin, gastrin 34 (G34, having 34 amino acids), gastrin 17 (G17, having 18 amino acids) and gastrin 14 (G14, having 14 amino acids). Gastrin (G34) stimulates stomach acid secretion and has a trophic effect on gastrointestinal tract (G.I) mucosa. Glycine-Extended Gastrin (Gly-G17) and amidated Gastrin (G17-NH2) also stimulate stomach acid secretion and exhibit a trophic effect on G.I. mucosa.
Gastrin functions in healthy adults are limited to preparing the gastrointestinal tract for the process of digesting ingested food. However, much recent research has implicated gastrin as a growth factor for some types of cancer (Baldwin et al., Gut 42:581-4, 1998; Smith et al., Aliment Pharmacol Ther 14:1231-47, 2000) including pancreatic, gastric, and colorectal carcinoma. Expression of gastrin and gastrin receptors has been demonstrated in primary tumors taken from cancer patients. Since some tumor types appear to produce and secrete their own gastrin, gastrin can act to stimulate tumor growth via autocrine and paracrine pathways as well as via an endocrine pathway. Several studies published in the literature have demonstrated that tumors taken from cancer patients both produce gastrin and express high levels of gastrin receptors (Schmitz et al., Eur J Clin Invest 31:812-20. 2001; Finley et al., Cancer Res 53:2919-26. 1993; Weinberg et al., J Clin Invest 100:597-603, 1997; Caplin et al., Br J Surg 87:1035-40, 2000).
The therapeutic approach of disrupting the gastrin-mediated mitogenesis of cancer cells has been tried in the clinic using small molecule antagonists to the gastrin receptor. Several small molecule antagonists for gastrin receptors have been tested in clinical trials for oncology indications.
Antibodies represent a powerful approach to neutralize therapeutic targets due to their high degree of specificity and affinity. Monoclonal antibodies specific for murine gastrin peptides have been disclosed in U.S. Pat. Nos. 6,861,510 and 5,688,506. However, these antibodies do not possess the desired specificity for human gastrin as needed for clinical therapy.
Thus there remains a need in the art to develop specific antibodies against human gastrin to use in the treatment of cancers and other conditions or disorders associated with gastrin expression.